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Preparation and Applications of Theranostic Nanomaterials

Preparation and Applications of Theranostic Nanomaterials
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Theranostics is an emerging research field for a simultaneous diagnostic therapy on the basis of advanced nano-bio fusion technology. Theranostic system is a new modality using real-time, non-invasive and in vivo imaging for therapy with nanomaterials. Nanomaterials such as silicon nanowire (Si-NW), carbon materials, quantaum dots (Qdots), iron oxide nanoparticles (IONPs) and gold nanoparticles have been widely investigated for diagnostic applications. In combination with therapeutics, these nanomaterials showed the feasibility to open a new era of theranostic nanomedicines. Nanomedicine is the term for the use of advanced nanobiotechnology for the development of medicines. After overall introduction in Chapter 1, three main topics were described on aptamer functionalized field effect transistor (FET) biosensors, real-time bioimaging of hyaluronic acid (HA) derivatives using Qdots, and theranostic systems using IONPs and polymeric micelles.In Chapter 2, aptamer biosensor, so called aptasensor, was fabricated, characterized, and applied to real-time electrical detection of target proteins for diagnostic applications using Si-NW and single wall nanotubes (SWNT) thin film. Si-NWs were surface-modified with 3-aminopropyl diethoxysilane and succinic anhydride to introduce amine and carboxyl groups on the Si surface. Aptamers with 5’-end amine groups were chemically grafted on the surface-modified Si-NW through amide bond formation. Atomic force microscopic (AFM) analysis confirmed the immobilization of aptamers on Si-NW and their binding with protein samples. Fluorescence micrograph visualized the FITC labeled protein after binding to aptamers immobilized on Si-NWs. The Si-NW FET aptamer biosensor was successfully applied to the real-time detection of electronic signals during and after binding with protein samples like thrombin and vascular endothelial growth factor (VEGF). Furthermore, aptamer functionalized addressable SWNT-film arrays between cantilever electrodes were successfully developed for biosensor applications. Electrophoretically aligned suspended SWNT films made possible highly specific and rapid detection of target proteins with a large binding surface area. Aptasensors using SWNT-film FET resulted in a real-time, label-free, and electrical detection of thrombin as a model protein molecule down to the concentration of pico-molar range with a step-wise rapid response time of several seconds.In Chapter 3, real time bio-imaging of HA derivatives was carried out using Qdots to assess the possibility of HA derivatives as novel target specific drug delivery carriers for the treatment of liver diseases. HA-QDot conjugates with HA modification of ca. 22 mol% was synthesized by amide bond formation between carboxyl groups of QDots and amine groups of adipic acid dihydrazide modified HA (HA-ADH). According to in vitro bioimaging, HA-QDot conjugates were taken up more effectively to liver disease cells of hepatic stellate cells and hepatoma cells than normal hepatocytes. After tail vein injection, HA-QDot conjugates were target-specifically delivered to the cirrhotic liver with a slow clearance longer than 8 days, whereas the clearance of HA-QDot conjugates was very rapid in normal mice within 3 days. The fluorescence intensity in dissected tissues confirmed the target specific delivery of HA-QDot conjugates to the liver in cirrhotic mice. Moreover, in vivo real-time confocal microscopy of HA-QDot conjugates clearly visualized the target specific delivery and accumulation of HA-QDot conjugates from the fluorescence-labeled blood vessels to the liver tissues. Taken together, we could confirm the feasibility of HA derivatives as a target specific intracellular drug delivery carrier for the treatment of liver diseases. As a model system, the target specific delivery of HA-interferon alpha conjugate was successfully visualized to the liver. In Chapter 4, theranostic systems were successfully developed using iron oxide nanoclusters (IONCs) and polymeric micelles. IONPs have been widely investigated as a contrast agent for magnetic resonance imaging (MRI). IONPs were prepared by the thermal decomposition method of iron-oleate complex. The dopamine modified HA (HA-DOPA) was prepared via conjugation between amine group of dopamine and carboxyl group of HA. The oil-soluble IONP was emulsified and aggregated in HA-DOPA by O/W emulsion. The resulting IONC was characterized with TEM and applied to target specific bio-imaging of MRI. In addition, polymeric micelles were prepared by the conjugation of HA with anti-Flt1 peptide to encapsulate doxorubicin and IONPs for cancer theranostic applications. Like IONP, doxorubicin was dispersed in chloroform, and encapsulated in the HA-Flt1 pep conjugate micelles. UV-Vis spectroscopy, DLS and TEM analyses confirmed the successful preparation of HA-Flt1 pep/DOX micelles. The theranostic micelles showed the feasibility for bioimaging for the treatment of liver cancer.
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